This is a proposal to explore in depth the biology of the artery wall in relation to the etiology and pathogenesis of atherosclerosis. This program studies endothelium, smooth muscle monocytes/macrophages, T cells, and platelets and their interrelationships in arterial biology anci atherogenesis, with particular emphasis on 1) understanding the growth factors, including platelet-derived growth factor (pDGF), derived from platelets, macrophages, endothelium, and smooth muscle in terms of the mechanisms by which they induce mitogenesis and chemotaxis and alter cell functions, such as adhesive interactions; 2) in vivo studies of atherogenesis and restenosis postangioplasty in hypercholesterolemic nonhuman primates and rabbits, and atherogenesis in transgenic mice; 3) the role of matrix metalloproteinases and heparin in the regulation of smooth muscle function in vitro and in vivo; 4) the role of a relatively recently discovered molecule, osteopontin, in its capacity as an adhesive molecule and as a stimulus for smooth muscle migration; 5) the adhesive interactions between leukocytes and endothelium and of smooth muscle in the processes of atherogenesis and inflammation; 6) factors that modulate and determine the nature of cholesterol and lipid trafficking in cells and the roles of these processes in intracellular cholesterol homeostasis and atherogenesis; 7) the role of proteoglycans in influencing proliferation, migration, and adhesive events in the genesis of the atherosclerotic plaque; 8) the regulation of vascular cell function by thrombospondins and SPARC and their roles in growth factor retention and modulation of cell/matrix interactions; 9) regulation of smooth muscle function by tyrosine phosphatases; and 10) studies to characterize intracellular signal transduction mechanisms activated by fluid flow over endothelial cells. All of these projects are interactive and relate to further testing and analysis of the Response-to-Injury Hypothesis of Atherosclerosis.